JP2007523932A - Skin whitening agent, composition and method - Google Patents

Abstract

The present invention provides a coumarin-derived compound of formula (I) alone or in combination with other skin benefit agents and as a skin lightening agent, together with a cosmetic vehicle: formula (I). Wherein _one or both of R ₁ and / or R ₂ is hydrogen (H); linear or branched, saturated or unsaturated, C ₁ -C ₁₂ alkyl, alkenyl, acyl or heteroalkyl (preferably R ₃ represents a linear or branched, cyclic or acyclic, saturated or unsaturated, C ₁ -C ₁₂ alkyl, alkenyl, cycloalkyl, cycloalkenyl or heteroalkyl group. R ₅ represents a hydrogen atom (H) or R ₄ ; R ₄ is a linear or branched, cyclic or acyclic, saturated or unsaturated, heteroatom-containing or non-containing C ₁ -C ₂₂ alkyl, alkenyl, cycloalkyl, cycloalkenyl, represents a heteroalkyl, aryl or heteroaryl group. The compounds, compositions and methods have effective skin whitening properties, may be even less irritating to the skin, are cost effective and are relatively easy to manufacture. Also provided is a method of making a compound of general formula (I) from a 4-substituted -7-hydroxycoumarin derivative.

Description

  The present invention relates to a coumarin-derived compound and a cosmetic composition containing the coumarin-derived compound, more specifically, a 4-substituted 7-hydroxycoumarin-derived compound, and their cosmetic use, for example, as a skin lightening agent. About.

  Many people are interested in the degree of skin pigmentation. For example, people with stains or freckles will want the spots with such pigments to be inconspicuous. Others may want to reduce the darkening of the skin caused by exposure to sunlight or to lighten the natural skin color. In order to meet this requirement, numerous attempts have been made to develop products that reduce pigment production in melanocytes. However, substances identified so far tend to be less effective or have undesirable side effects such as toxicity or skin irritation. Accordingly, there is always a need for new skin lightening agents with improved overall effectiveness and agents that help facilitate processing in their manufacture.

  Resorcinol derivatives have advantages for skin and hair beauty. Certain resorcinol derivatives, particularly 4-substituted resorcinol derivatives, are useful in cosmetic compositions for providing skin whitening effects. Resorcinol derivatives are described in Torihara et al., US Pat. No. 4,959,393; Hu et al., US Pat. No. 6,132,740; Bradley et al., US Pat. No. 6,504,037; and Japanese published patent application JP2001. It is described in many documents such as 010925 and JP2000-327557. The resorcinol derivative is a known compound, and a method of condensing a saturated carboxylic acid and resorcinol in the presence of zinc chloride and reducing the resulting condensate with zinc amalgam / hydrochloric acid (Lille, et al., Tr. Nauch- Inslt Slantsev 1969, No. 18: 127-134), or a method of reacting resorcinol with a corresponding alkyl alcohol at a high temperature of 200 to 400 ° C. in the presence of an alumina catalyst (UK Patent 1,581). , No. 428), etc., can be easily obtained. Skin lightening compounds that can be derived from coumarin are disclosed in US Patent Publication No. 2004/0042983. Some of these compounds can irritate the skin.

  Applicants have discovered in the present invention that the use of a compound that can be derived from a coumarin derivative (but not necessarily derived from a coumarin derivative) provides a skin whitening effect. The general chemical formulas and structures of these compounds are discussed in more detail below. Similar to resorcinol derivatives, hydroxycoumarin derived compounds, and especially 4-substituted 7-hydroxycoumarin derived compounds, are found to be effective, probably less irritating to the skin and relatively simple to manufacture. It was done. These compounds are referred to herein as “coumarin-derived resorcinol derivatives”. The coumarin-derived resorcinol derivatives of the present invention have not been used so far for personal care or especially for skin whitening.

  The compounds of general formula I and compositions comprising said compounds provide cosmetic benefits, in particular a skin lightening effect, which can be less irritating and relatively easy to manufacture. In addition to the cosmetically acceptable vehicle, the present invention relates to the weight of the composition of formula I:

（Ｒ_１及び／又はＲ_２の一方又は両方が、水素（Ｈ）；直鎖又は分岐の、飽和又は不飽和の、Ｃ_１−Ｃ_１２アルキル、アルケニル、アシル又はヘテロアルキル（例えば、好ましくは、アルコキシ）基を表す。）
の化合物を、０．０００００１ないし５０重量％含む組成物を使用する、皮膚美白の美容方法を提供する。 好ましくは、Ｒ_１及び／又はＲ_２の一方又は両方が、水素（Ｈ）；直鎖又は分岐、飽和又は不飽和の、Ｃ_１−Ｃ_１２アルキル又はアシル基を表す。より好ましくは、Ｒ^１及びＲ^２の両方が水素を表し、並びに
Ｒ^３は、直鎖又は分岐の、環式又は非環式の、飽和又は不飽和の、Ｃ_１−Ｃ_１２アルキル、アルケニル、シクロアルキル、シクロアルケニル又はヘテロアルキル基を表す。好ましくは、Ｒ^３は、アルキル基を表す。より好ましくは、Ｒ_３は、Ｃ_１アルキル基（すなわち、メチル基）を表し；及び
Ｒ_５は、水素原子（Ｈ）又はＲ_４を表す。好ましくは、Ｒ_５は、水素を表す。

(One or both of R ₁ and / or R ₂ is hydrogen (H); linear or branched, saturated or unsaturated, C ₁ -C ₁₂ alkyl, alkenyl, acyl or heteroalkyl (eg, preferably Represents an alkoxy) group.)
There is provided a cosmetic method for skin whitening using a composition comprising 0.000001 to 50% by weight of the above compound. Preferably, one or both of R ₁ and / or R _{2 represents} hydrogen (H); a linear or branched, saturated or unsaturated, C ₁ -C ₁₂ alkyl or acyl group. More preferably, both R ¹ and R ² represent hydrogen and R ³ is linear or branched, cyclic or acyclic, saturated or unsaturated, C ₁ -C ₁₂ alkyl, alkenyl, Represents a cycloalkyl, cycloalkenyl or heteroalkyl group. Preferably R ³ represents an alkyl group. More preferably, R ₃ represents a C ₁ alkyl group (ie a methyl group); and R ₅ represents a hydrogen atom (H) or R ₄ . Preferably R ₅ represents hydrogen.

R ₄ is a linear or branched, cyclic or acyclic, saturated or unsaturated, heteroatom-containing (eg furan, dihydrofuran, pyran) or non-containing C ₁ -C ₂₂ alkyl, alkenyl Represents a cycloalkyl, cycloalkenyl, heteroalkyl, aryl or heteroaryl group. Preferably R ₄ represents a linear or branched, cyclic or acyclic, saturated or unsaturated, C ₁ -C ₂₂ alkyl group.

In the most preferred embodiment, each R ₁ , R ₂ and R ₅ represents H, while R ₃ represents a methyl group. That is, a compound of formula II herein.

These 4-methyl 7-hydroxycoumarin-derived compounds or coumarin-derived resorcinol derivatives can be prepared by hydrolysis after catalytic (nickel or palladium catalyst) hydrogenation of 4-substituted 7-hydroxy-coumarins. . The hydroxy group (when any of R ₁ , R ₂ and R ₅ represents H) can be further substituted by methods known in the art, such as by esterification.

  Thus, the present invention

（Ｒ_３は、直鎖又は分岐の、環式又は非環式の、飽和又は不飽和の、Ｃ_１−Ｃ_１２アルキル、アルケニル、シクロアルキル、シクロアルケニル又はヘテロアルキル基を表し；
Ｒ_４は、直鎖又は分岐の、環式又は非環式の、飽和又は不飽和の、複素原子含有又は非含有の、Ｃ_１−Ｃ_２２アルキル、アルケニル、シクロアルキル、シクロアルケニル、ヘテロアルキル、アリール又はヘテロアリール基を表す。）を含む、Ｂ、Ｃ、Ｄ及びこれらの混合物からなる群から選択される一般式を有する化合物を作製する方法を提供する。

(R ₃ represents a linear or branched, cyclic or acyclic, saturated or unsaturated, C ₁ -C ₁₂ alkyl, alkenyl, cycloalkyl, cycloalkenyl or heteroalkyl group;
R ₄ is linear or branched, cyclic or acyclic, saturated or unsaturated, heteroatom-containing or non-containing, C ₁ -C ₂₂ alkyl, alkenyl, cycloalkyl, cycloalkenyl, heteroalkyl, Represents an aryl or heteroaryl group. And a compound having a general formula selected from the group consisting of B, C, D, and mixtures thereof.

  The method further comprises the general formula I:

（Ｒ_１及び／又はＲ_２の一方又は両方が、水素（Ｈ）；直鎖又は分岐の、飽和又は不飽和の、Ｃ_１−Ｃ_１２アルキル、アルケニル、アシル又はヘテロアルキル基を表す。）
の化合物を与えるために、フェニル環の１，３−ヒドロキシ位の置換を含み得る。

(One or both of R ₁ and / or R _{2 represent} hydrogen (H); a linear or branched, saturated or unsaturated, C ₁ -C ₁₂ alkyl, alkenyl, acyl, or heteroalkyl group.)
To give a 1,3-hydroxy substitution on the phenyl ring.

  Additional skin benefit agents such as α-hydroxy acids, β-hydroxy acids, polyhydroxy acids, hydroquinones, t-butylhydroquinones, vitamin C derivatives, diacids, retinoids; resorcinol derivatives, and mixtures thereof may be included in the composition. Can be included. Organic and inorganic sunscreens can also be included.

  The use of a compound that can be derived from a coumarin derivative (but not limited to a compound derived from a coumarin derivative) provides a skin whitening effect. The general chemical formulas and structures of these compounds are discussed in more detail below. 4-Substituted 7-hydroxycoumarin derived compounds have been found to be effective cosmetic agents, particularly skin lightening agents, and are relatively simple to manufacture.

  As used herein, the term “cosmetic composition” is intended to describe a composition for topical application to human skin.

  As used herein, the term “skin” includes skin on the face, neck, chest, back, arms, arms, hands, feet and scalp.

  Except for the examples, or unless otherwise indicated, all numbers in this specification indicating the amount of material or reaction conditions, physical properties and / or use of the material are “about It should be understood that it is modified by the term "." All amounts are relative to the weight of the composition unless otherwise stated.

  It should be noted that when specifying an arbitrary range of concentrations, some upper concentration can be accompanied by any lower concentration.

  For the avoidance of doubt, the word “comprising” means including, not necessarily consisting of or consisting of. In other words, the listed processes or options need not be exclusive.

The present invention relates to compounds of the general formula I, compositions comprising said compounds and in particular their cosmetic use as skin lightening agents. A particular advantage of the compositions and methods is that the compounds of general formula I can be less irritating to the skin than other skin lightening compounds (even skin lightening compounds with a similar structure) It is easy to manufacture.

  A most preferred embodiment is a compound of formula II:

によって表される。

Represented by

  This most preferred embodiment (referred to herein as a 4-methyl 7-hydroxycoumarin derived compound or coumarin derived resorcinol derivative) is the catalytic (nickel or palladium catalyst, 4-methyl 7-hydroxycoumarin, Preferably it can be prepared by hydrolysis after Pd on carbon base, ie Pd / C) hydrogenation. The hydroxy group can be further substituted by methods known in the art, such as by esterification. Other methods of deriving the compound can also be utilized and the invention is not limited by the method of preparation.

  The composition generally contains 0.000001 to 50% of a coumarin-derived compound of general formula I based on the weight of the composition. Compounds of formula II are preferred. The amount of the coumarin-derived compound is preferably in the range of 0.00001% to 10% by weight, more preferably 0.001 to 7% by weight, most preferably 0.01 to 5% by weight of the total amount of the cosmetic composition. is there.

  Additional skin benefit agents can be included in the compositions useful for the method. Organic and inorganic sunscreens can also be included.

Process Synthesis Procedure 1.4 Hydrogenation of 4-Substituted -7-Hydroxycoumarin

General Procedure In a high pressure reaction vessel, a compound of general formula A (4-substituted-7-hydroxycoumarin (preferably 4), in a suitable solvent (eg, acetic acid, alcohol, organic solvent and mixtures thereof). -Alkyl-7-hydroxycoumarin)) and a catalyst (e.g. homogeneous or heterogeneous catalyst such as Pd and / or Ni and mixtures thereof attached to a suitable matrix) is added. When the reactor is pressurized with hydrogen (eg 690 kPa to 5.5 MPa [100 to 800 psi]) and monitored using appropriate analytical methods (eg TLC, GC, LC, hydrogen consumption and combinations thereof) , Stirring at 25 ° C. or higher (eg, 25 ° C. to 60 ° C.) until complete consumption of 4-substituted-7-hydroxycoumarin (preferably 4-alkyl-7-hydroxycoumarin) is observed. The reaction mixture is filtered through an insoluble support (eg, Celite ^™ , silica gel and combinations thereof), the solvent is removed under reduced pressure, and the product is purified using purification methods such as recrystallization, distillation, and combinations thereof. Is purified.

Specific Procedure / Preferred Embodiment:
7-hydroxy-3,4-dihydro-4-methylcoumarin (B1)
A Parr hydrogenator (1 L) was charged with 7-hydroxy-4-methylcoumarin, ie the compound of formula A1, (60 g, 0.34 mol) and acetic acid (350 mL). A suspension of 10% Pd / C (6.0 g) in acetic acid (150 mL) was added and the reactor was sealed, degassed and purged with nitrogen (4 ×). The reactor was pressurized with hydrogen to 2.2 MPa (320 psi) and stirred at 30 ° C. for 16 hours, but at this point no hydrogen was consumed and the starting material was consumed to clean the product. Formed by TLC (4% methanol: chloroform). The reactor was evacuated, purged with nitrogen, and the mixture was filtered through Celite ^™ . The solvent was removed to give a white solid (60.5 g, 100%). Recrystallization from ethyl acetate: hexane gave the pure product as a white solid. Melting point 109-110 ° C .; ¹ H NMR (DMSO-d ₆ ) d1.19 (d, JJ = 6.7, 3H), 2.52 (dd, JJ = 15.9, 7.3, 1H), 2 .84 (dd, JJ = 15.9, 5.5, 1H), 3.08 (m, 1H), 6.46 (d, JJ = 2.4, 1H), 6.58 (dd, JJ = ^{8.2,2.4,1H), 7.10 (d, JJ} = 8.2,1H), 9.66 (s, 1H); 13 C (DMSO-d 6) d19.84,27.87 , 36.45, 103.17, 111.38, 118.29, 127.17, 151.45, 157.17, 168.11; m / z (EI; TMS derivatization; M ⁺ ) 250; IR ( neat; cm ⁻¹ ) 3379.6, 2969.2, 2930.2, 2871.5, 1748.0, 1630.7, 1601.4, 1518.4, 1454.89, 1352.3, 1283.9, 1249.7, 1239.9, 1152.0, 1117.8, 1078.7, 1020.1, 995.7, 942. 0, 854.0, 814.9.

II. Hydrolysis of 4-substituted 3,4-dihydro-7-hydroxycoumarin

General Procedure A compound of general formula B, i.e. 4-substituted 3,4-dihydro-7-hydroxycoumarin, is suspended in water and the hydroxide ion equivalent reagent (e.g. sodium hydroxide) is suspended. , Potassium hydroxide, polymer-bonded carbonate and combinations thereof). The reaction is monitored using appropriate analytical methods (eg, TLC, GC, LC, and combinations thereof) until the starting material is completely consumed. The reaction mixture is cooled (eg, a temperature of 0-10 ° C.) and acidified with a hydrogen ion equivalent reagent (eg, hydrochloric acid) until the pH of the solution reaches 1 or less. Extract the solution with a suitable organic solvent (eg, diethyl ether), dry the organic layer with an insoluble desiccant (eg, sodium sulfate), filter, and remove the solvent. For example, the product is purified using purification methods such as recrystallization, distillation, chromatography, or combinations thereof.

Specific Procedure / Preferred Embodiment
3- (2,4-Dihydroxyphenyl) -butyric acid (compound of general formula II)
To a suspension of 7-hydroxy-3,4-dihydro-4-methylcoumarin (compound of formula B1) (8.0 g, 45 mmol) in water (40 mL) was added sodium hydroxide (5.0 M, 27 mL, 135 mmol). Add at room temperature (20 ° C.) and stir the resulting solution for 20 minutes. At this point, the starting material was consumed and the product formed cleanly as indicated by TLC (4% methanol: chloroform). The solution was cooled to 5 ° C. and carefully acidified with concentrated HCl so that the pH was below 1 while keeping the temperature below 15 ° C. throughout the addition. Extract the solution with diethyl ether (4 × 100 mL), wash the organic layer with saturated NaCl (4 × 50 mL), combine, dry (Na ₂ SO ₄ ), filter, remove the solvent, A pale orange oil was obtained. Further purification by filtration through a short pad of silica gel and elution with ethyl acetate gave the pure product as a white solid (8.3 g, 94%). Melting point 92-94 ° C .; ¹ H NMR ((DMSO-d ₆ ) d1.13 (d, JJ = 7.0, 3H), 2.33 (dd, JJ = 15.0, 8.9, 1H), 2.52 (dd, JJ = 15.5, 7.3, 1H), 3.32 (m, 1H), 6.16 (dd, JJ = 8.2, 2.4, 1H), 6.28 (D, JJ = 2.4, 1H), 6.84 (d, JJ = 8.2, 1H), 9.08 (s, 1H), 9.59 (s, 1H), 11.87 (s ^13C NMR (DMSO-d ₆ ) d20.39, 28.97, 41.0, 102.58, 106.01, 122.55, 127.27, 155.19, 156.18, 173 .74; m / z (EI; TMS ^{derivatized: M +) 412; IR (} neat; cm -1) 3360.1,2974.1,293 .1,2877.4,1748.0,1713.8,1625.9,1606.3,1518.4,1459.8,1381.6,1347.4,1283.9,1254.6,1239.9 1156.9, 1117.8, 1025.0, 981.0, 937.1, 849.1, 810.1.

III. Esterification of 4-substituted 3,4-dihydro-7-hydroxycoumarin

General Procedure A compound of general formula B, i.e. 4-substituted-3,4-dihydro-7-hydroxycoumarin, is dissolved in a selected alcohol or the coumarin and alcohol are dissolved in a suitable solvent (e.g. , Tetrahydrofuran). Add acid catalyst (eg sulfuric acid, acidic resin or combinations thereof) and use appropriate analytical methods (eg TLC, GC, LC or combinations thereof) until the starting material is completely consumed To monitor. The reaction mixture is partially neutralized (to a pH of 4 to 7) using a mild base (eg, aqueous sodium bicarbonate) and washed with a suitable organic solvent (eg, diethyl ether) and water. Distributed between. The organic layer is dried using an insoluble desiccant (eg, sodium sulfate), filtered, and the solvent removed under reduced pressure. For example, the product is purified using purification methods such as recrystallization, distillation, chromatography and / or combinations thereof.

Specific Procedure / Preferred Embodiment:
3- (2,4-Dihydroxyphenyl) -methyl butyrate (D1)
To a solution of 7-hydroxy-3,4-dihydro-4-methylcoumarin (B1) (75.8 g, 430 mmol) in methanol (1 L) was added concentrated sulfuric acid (1.2 mL, 43 mmol) at room temperature, The solution was stirred for 16 hours. At this point, the starting material was consumed and the product formed cleanly as indicated by TLC (8% methanol: chloroform). The solution was neutralized with 7% NaHCO ₃ (50 mL) and most of the solvent (750 mL) was removed under reduced pressure. The solution is diluted with ethyl acetate (1 L), washed successively with saturated NaHCO ₃ : saturated NaCl (1: 1, 200 mL), saturated NaCl (2 × 200 mL), dried (Na ₂ SO ₄ ) and filtered. The solvent was removed to give an orange oil. Further purification by filtration through a short pad of silica gel and elution with 5% methanol in chloroform gave the pure product as a pale orange gel (87 g, 98%). ¹ H NMR (DMSO-d ₆ ) d1.13 (d, JJ = 7.0, 3H), 2.42 (dd, JJ = 15.0, 8.9, 1H), 2.58 (dd, JJ = 15.0, 5.8, 1H), 3.37 (m, 1H), 3.55 (s, 3H), 6.15 (dd, JJ = 8.6, 2.4, 1H), 6 .28 (d, JJ = 2.4, 1H), 6.84 (d, JJ = 8.2, 1H), 8.93 (s, 1H), 9.11 (s, 1H); ¹³ C NMR _(DMSO-d 6) d20.16,29.09,40.77,51.00,102.55,106.02,122.09,127.04,155.18,156.27,172.55; m / z (EI; TMS derivatization; M ⁺ ) 354; IR (neat; cm ⁻¹ ) 3384.5, 2969.3, 1708.9, ¹ 621.0, 1606.3, 1518.4, 1454.9, 1367.0, 1303.5, 1220.4, 1166.7, 1108.1, 976.2, 839.4, 810.1.

A skin benefit agent that is used as needed A preferred cosmetic composition is a cosmetic composition that is suitable for application to human skin according to the method of the present invention, the composition optionally, but Preferably, it contains a skin benefit agent in addition to the coumarin-derived compound.

  Further suitable skin benefit agents include anti-aging agents, wrinkle reducing agents, skin lightening agents, acne inhibitors and sebum inhibitors. Examples of these include α-hydroxy acids, β-hydroxy acids, polyhydroxy acids, hydroquinone, t-butylhydroquinone, vitamin C derivatives, diacids, retinoids; betulinic acid; allantoin, placental extracts; and other resorcinol derivatives Is included.

Cosmetically acceptable carrier A cosmetically acceptable vehicle is a diluent (for skin benefit ingredients in the composition) to facilitate the distribution of skin benefit ingredients when the composition is applied to the skin. dilutant), can act as a dispersant or carrier.

  The vehicle can be aqueous, anhydrous or an emulsion. Preferably, the composition is an aqueous or emulsion, in particular a water-in-oil or oil-in-water emulsion, preferably an oil-in-water emulsion. Water, if present, can be in an amount that can vary from 5 to 99%, preferably from 20 to 70%, optimally from 40 to 70%, based on the weight of the cosmetic composition.

In addition to water, relatively volatile solvents can also serve as carriers in the compositions of the present invention. Most preferred is a monovalent C ₁ -C ₃ alkanol. These include ethyl alcohol, methyl alcohol and isopropyl alcohol. The amount of monovalent alkanol can range from 1 to 70%, preferably from 10 to 50%, optimally from 15 to 40% by weight of the cosmetic composition.

  An emollient material may also serve as a cosmetically acceptable carrier. These can be in the form of silicone oils and synthetic esters. The amount of emollient can range from 0.1 to 50%, preferably 1 and 20% by weight of the cosmetic composition.

Silicone oils can be divided into volatile and non-volatile types. As used herein, the term “volatile” refers to a material having a vapor pressure that can be measured at room temperature. The volatile silicone oil is preferably selected from cyclic polydimethylsiloxane or linear polydimethylsiloxane containing from 3 to 9, preferably from 4 to 5, silicon atoms. Linear volatile silicone materials generally have viscosities less than 5 centistokes (5 × 10 ⁻⁶ m ² s ⁻¹ ) at 25 ° C., whereas cyclic materials typically It has a viscosity of less than 10 centistokes (1 × 10 ⁻⁵ m ² s ⁻¹ ). Nonvolatile silicone oils useful as emollient materials include polyalkyl siloxanes, polyalkylaryl siloxanes and polyether siloxane copolymers. Substantially non-volatile polyalkylsiloxanes useful in the present invention include, for example, from 25 to 25 million centistokes (approximately 5 × 10 ⁻⁶ m ² / sec to 25 m ² / sec) at 25 ° C. Polydimethylsiloxane having a viscosity of Preferred non-volatile emollients useful in the compositions of the present invention include a viscosity of 10 to 400 centistokes (1 × 10 ⁻⁵ m ² / sec to about 4 × 10 ⁻⁴ m ² / sec) at 25 ° C. There are polydimethylsiloxanes.

As an ester emollient,
(1) There are alkenyl or alkyl esters of fatty acids having 10 to 20 carbon atoms. Examples include isoarachidyl neopentanoate, isononyl isonanoate, oleyl myristate, oleyl stearate and oleyl oleate.

  (2) Ether-esters such as fatty acid esters of ethoxylated fatty alcohols.

  (3) Polyhydric alcohol ester. Ethylene glycol mono and di fatty acid esters, diethylene glycol mono and di fatty acid esters, polyethylene glycol (200-6000) mono and di fatty acid esters, propylene glycol mono and di fatty acid esters, polypropylene glycol 2000 monooleate, polypropylene glycol 2000 monostearate, ethoxylated Propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol polyfatty esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol distearate, Polyoxyethylene polyol fatty acid ester, sorbitan fatty acid ester, and polyoxyethylene sorbitan fatty acid ester , It is an excellent polyhydric alcohol ester.

  (4) Wax esters such as beeswax, spermaceti, myristyl myristate, stearyl stearate and arachidyl behenate.

  (5) Sterol esters and cholesterol fatty acid esters are examples.

  Fatty acids having from 10 to 30 carbon atoms can also be included as cosmetically acceptable carriers for the compositions of the present invention. Examples of this category are pelargonic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, hydroxystearic acid, oleic acid, linoleic acid, ricinoleic acid, arachidonic acid, behenic acid and erucic acid.

  The polyhydric alcohol type humectant can also be used as a cosmetically acceptable carrier in the composition of the present invention. Moisturizers help increase the effectiveness of emollients, reduce desquamation, stimulate the removal of accumulated scales and improve skin feel. Typical polyhydric alcohols include propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol and their derivatives, sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1,3-butylene glycol, 1,2,6-hexane. Included are glycerol, polyalkylene glycols, more preferably alkylene polyols, and derivatives thereof, such as triols, ethoxylated glycerol, propoxylated glycerol and mixtures thereof. For best results, the humectant is preferably propylene glycol or sodium hyaluronate. The amount of humectant can range anywhere from 0.5 to 30%, preferably 1 to 15%, based on the weight of the cosmetic composition.

  Concentrating agents can also be used as part of the cosmetically acceptable carrier of the composition according to the invention. Typical thickeners include cross-linked acrylic esters (eg, Carbopol 982), hydrophobically modified acrylic esters (eg, Carbopol 1382), cellulose derivatives and natural rubber. Useful cellulose derivatives include sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose and hydroxymethylcellulose. Natural rubbers suitable for the present invention include guar, xanthan, sclerotium, carrageenan, pectin and combinations of these rubbers. The amount of thickening agent can range from 0.0001 to 5%, usually from 0.001 to 1%, optimally from 0.01 to 0.5%, based on the weight of the cosmetic composition.

  Overall, water, solvent, silicone, ester, fatty acid, humectant and / or concentrate are in an amount of 1 to 99.9%, preferably 80 to 99%, based on the weight of the cosmetic composition. Will constitute a cosmetically acceptable carrier.

  Depending on the average hydrophilic-lipophilic balance (HLB) of the emulsifier used, oils and oily materials may be present along with the emulsifier to provide either a water-in-oil emulsion or an oil-in-water emulsion. .

Surfactants may also be present in the cosmetic composition of the present invention. The total surfactant concentration can range from 0.1 to 40%, preferably from 1 to 20%, optimally from 1 to 5%, by weight of the composition. The surfactant may be selected from the group consisting of anionic, nonionic, cationic and amphoteric active substances. Particularly preferred nonionic surfactants are C ₁₀ -C ₂₀ fatty alcohols or acid hydrophobic substances condensed with 2 to 100 moles of ethylene oxide or propylene oxide per mole of hydrophobic substance; mono- and di-fatty acid esters of ethylene glycol; fused _C 2 _{-C 10} alkyl phenols fatty acid monoglyceride; sorbitan, mono- and di _-C 8 _{-C 20} fatty acid; block copolymer (ethylene oxide / propylene oxide); and polyoxyethylene A nonionic surfactant having sorbitan as well as a mixture thereof. Alkyl polyglycosides and saccharide fatty amides (eg methyl gluconamides) are also suitable nonionic surfactants.

Preferred anionic surfactants include soaps, alkyl ether sulfates and sulfonates, alkyl sulfates and sulfonates, alkylbenzene sulfonates, alkyl and dialkylsulfosuccinates, C ₈ -C ₂₀ acyl isethionates, acyl glutamates _include C 8 _{-C 20} alkyl ether phosphates and combinations thereof.

Components Used as Needed In the cosmetic composition of the present invention, a plasticizer; a calamine; an antioxidant; a chelating agent; and a sunscreen can be added as necessary.

  Other auxiliary trace ingredients can also be incorporated into the cosmetic composition. These ingredients can include colorants, pigments, opacifiers and perfumes. The amount of these other auxiliary minor components can be in any range from 0.001% up to 20% based on the weight of the composition.

When used as a sunscreen, the metal oxides can be used alone or in a mixture and / or in combination with an organic sunscreen. Examples of organic sunscreens include, but are not limited to those listed in the table below.

The amount of organic sunscreen in the cosmetic composition is preferably in the range of 0.1% to 10% by weight, more preferably 1% to 5% by weight. Preferred organic sunscreens are PARSOL ^™ MCX and PARSOL ^™ 1789 due to their effectiveness and commercial availability.

Use of the composition The method of the present invention is mainly applied topically to human skin to whiten the skin, to reduce the degree of pigmentation in the skin, and / or to make the skin tone uniform. The purpose is to use personal care products.

  In use, from a suitable container or applicator, a small amount of the composition, eg, 1 to 5 mL, is applied to the exposed area of the skin and, if necessary, then using hands or fingers or a suitable device. Spread on the skin and / or smear into the skin.

Product Form and Packaging The cosmetic composition of the present invention is a liquid having a viscosity (at 20 ° C.) of 10,000 to 20,000 mPas as a lotion having a viscosity (at 20 ° C.) of 4,000 to 10,000 mPas. It can be formulated as a cream or as a cream having a viscosity (at 20 ° C.) from 20,000 to 100,000 mPas or higher. In order to be compatible with its viscosity and intended use by consumers, the composition can be packaged in a suitable container. For example, lotions or liquid creams can be packaged in containers equipped with bottles or rotating ball applicators or aerosol devices driven by propellants or pumps suitable for finger operation. If the composition is a cream, it can simply be stored in a non-deformable bottle or squeeze container, such as a tube or a jar with a lid. If the composition is a solid or semi-solid stick, it can be manually or mechanically discharged into a suitable container for discharging or extruding.

  The present invention therefore also provides a sealed container containing a cosmetically acceptable composition as defined herein.

  The following examples are intended to illustrate the principles of the invention and are not intended to be limiting in order to illustrate the best mode of carrying out the invention.

Example 1
Throughout the examples described below, the following compounds prepared according to the procedures described in this example were used.

  As follows, a compound of formula A1 (referred to herein as 4-methyl 7-hydroxycoumarin) was used as a starting material for preparing the coumarin-derived resorcinol compound according to the present invention.

(Example 2)
A cosmetic composition belonging to the scope of the present invention was prepared.

  The basic formulations shown in the table below were made by heating the Phase A component to 70-85 ° C. with stirring. With stirring, the Phase B component was heated in a separate vessel until 70-85 ° C. Phase A was then added to Phase B while keeping both phases at 70-85 ° C. The mixture was stirred at 70-85 ° C. for at least 15 minutes and then cooled.

(Example 3)
Additional cosmetic compositions were prepared that were within the scope of the present invention.

実施例３の組成物は、以下のように調製した。

The composition of Example 3 was prepared as follows.

1. 1. Heat Phase A to 80 ° C. 2. Heat Phase B to 75 ° C. in a separate container. Add B to A, stop heating and mix for 30 minutes At 4.50 ° C. add Phase C and mix for 10 minutes.

(Example 4-11)
A group of additional compositions useful in the methods of the present invention that are within the scope of the present invention have been prepared and listed in the table below. The composition was prepared using the method described in Example 3.

Example 12 Cell-Based Assay This example demonstrates the skin whitening effect of using a 4-methyl 7-hydroxycoumarin derived resorcinol compound as a skin whitening agent according to the method described above. This experiment was performed using a cell-based assay.

In order to evaluate the effect of skin lightening agents, B16 mouse malignant melanoma cells were used in the following experiments. B16 cells were seeded at a density of 5000 cells / well in 96 well microtiter plates and 37% in Dulbecco's modified Eagle's medium (no phenol red) containing 10% fetal bovine serum and 1% penicillin / streptomycin. Incubated overnight at 5 ° C. in the presence of 5% CO ₂ . After 24 hours, this medium was replaced with fresh growth medium containing the treatment. All cultures were incubated for 72 hours, at which point melanin could be seen during the control treatment. Melanin containing medium was quantified by transferring to a clean 96 well plate and reading the absorbance at 530 nm. To confirm that the decrease in melanin was not a result of cytotoxicity, cell viability was assessed by measuring lactate dehydrogenase levels.

上に一覧されている結果から、本発明のクマリン由来レゾルシノール化合物が、４−エチルレゾルシノールと概ね同じ程度まで、メラニン合成を抑制するように見える。

From the results listed above, it appears that the coumarin-derived resorcinol compound of the present invention inhibits melanin synthesis to approximately the same extent as 4-ethylresorcinol.

Example 13 Mushroom Tyrosinase Assay Mushroom tyrosinase inhibition is an indicator of decreased melanin synthesis, thereby indicating a skin whitening effect. This experiment shows the efficacy of the coumarin-derived resorcinol derivative of the present invention.

  Phosphate buffer 150 μL (100 mM, pH 7.0), L-DOPA 10 μL (L-3,4-dihydroxyphenylalanine, 10 mM), and skin lightening agent 20 μL (dissolved in ethanol as a control) were 96 wells. Added into each well of the plate. Following the initial measurement of background absorbance at 475 nm, 20 μL of mushroom tyrosinase (Sigma T-7755; 6050 units / mL) was added and incubated at room temperature.

  Absorbance was read at 475 nm at the following time points: 0, 2, 4 and 6.5 minutes. This data is plotted as 475 nm absorbance vs. time (min) and the slope of the line is calculated (ΔAbs 475 nm / min). Values are expressed as a percentage of each untreated ethanol control reaction.

  The data show that the coumarin-derived compounds of Formula II and D1 are substantially as effective as 4-ethylresorcinol, and both compounds have excellent skin whitening effects. The 7-hydroxy-3,4-dihydro-4-methylcoumarin (B1) compound from which the compounds of the invention can be obtained is not very effective for skin whitening as measured by mushroom tyrosinase assay.

Claims (18)

Formula I

(One or both of R ₁ and / or R ₂ represents hydrogen (H); a linear or branched, saturated or unsaturated, C ₁ -C ₁₂ alkyl, alkenyl, acyl or heteroalkyl group;
R ₃ represents a linear or branched, cyclic or acyclic, saturated or unsaturated, C ₁ -C ₁₂ alkyl, alkenyl, cycloalkyl, cycloalkenyl or heteroalkyl group;
R ₅ represents a hydrogen atom (H) or R ₄ :
R ₄ is linear or branched, cyclic or acyclic, saturated or unsaturated, heteroatom-containing or non-containing, C ₁ -C ₂₂ alkyl, alkenyl, cycloalkyl, cycloalkenyl, heteroalkyl, Represents an aryl or heteroaryl group. )
Compound. _2. A compound according to claim 1, wherein R < ₁ > and R < ₂ > both represent hydrogen. Said compound is of formula II:

The compound of Claim 2 which is a compound of these. The compound according to any one of claims 1 to 3, wherein the compound is a 4-methyl 7-hydroxycoumarin-derived resorcinol derivative. a. 0.000001 to 50% by weight of the compound according to any one of claims 1 to 4;
b. A cosmetically acceptable carrier;
A cosmetic composition comprising:   The cosmetic composition according to claim 5, wherein the compound comprises 0.00001% to 10% by weight of the composition.   The cosmetic composition of claim 6, wherein the compound comprises 0.001% to 7% by weight of the composition.   The cosmetic composition according to claim 7, wherein the compound comprises 0.01% to 5% by weight of the composition.   The cosmetic composition according to any one of claims 5 to 8, wherein the composition further comprises a sunscreen.   The cosmetic composition according to claim 9, wherein the sunscreen agent is a finely divided metal oxide. The sunscreen agent is benzophenone-3, benzophenone-4, benzophenone-8, DEA, methoxycinnamate, dihydroxypropyl-PABA ethyl, PABA glyceryl, homosalate, methyl anthranilate, octocrylene, dimethyl PABA octyl, octyl methoxycinnamate (PARSOL ^™ MXC), octyl salicylate, PABA, 2-phenylbenzimidazole-5-sulfonic acid, TEA salicylic acid, 3- (4-methylbenzylidene) -camphor, benzophenone-1-, benzophenone-2, benzophenone-6, benzophenone From the group consisting of -12,4-isopropyldibenzoylmethane, butylmethoxydibenzoylmethane (PARSOL ^™ 1789), etoctylene and mixtures thereof 10. Cosmetic composition according to claim 9, which is a selected organic sunscreen.   A skin benefit wherein the composition is selected from the group consisting of α-hydroxy acids, β-hydroxy acids, polyhydroxy acids, hydroquinones, t-butylhydroquinones, vitamin C derivatives, diacids, retinoids, resorcinol derivatives and mixtures thereof. The cosmetic composition according to any one of claims 5 to 11, further comprising an agent.   A cosmetic method for skin whitening, comprising applying the composition according to any one of claims 5 to 12 to the skin.   Use of a compound according to any one of claims 1 to 4 for skin whitening. Formula A

(R ₃ represents a linear or branched, cyclic or acyclic, saturated or unsaturated, C ₁ -C ₁₂ alkyl, alkenyl, cycloalkyl, cycloalkenyl or heteroalkyl group). Reacting with hydrogen in the presence of a catalyst,
Formula B

A method for producing the compound of (I) making a compound of formula B by the method of claim 15;
(Ii) reacting the compound of formula B with a hydroxide ion equivalent;
(Iii) acidifying with hydrogen ion equivalent;
Including the general formula C

A method for producing the compound of (I) making a compound of formula B by the method of claim 15;
(Ii) the compound of formula B is substituted with formula R ₄ OH (R ₄ is linear or branched, cyclic or acyclic, saturated or unsaturated, heteroatom-containing or non-containing C _1- Reacting with a compound having a C ₂₂ alkyl, alkenyl, cycloalkyl, cycloalkenyl, heteroalkyl, aryl or heteroaryl group);
Including the general formula D

A method for producing the compound of (I) producing a compound having the general formula C by the method of claim 16 or producing a compound having the general formula D by the method of claim 17;
(Ii) substituting the 1-hydroxy position, the 3-hydroxy position, or both the 1- and 3-hydroxy positions of the phenyl ring of the compound having the general formula C or D;
Including
R ₁ and R ₂ both represent a linear or branched, saturated or unsaturated, C ₁ -C ₁₂ alkyl, alkenyl, acyl or heteroalkyl group, or _one of R ₁ and R ₂ is a hydrogen atom ( H) and the other of R ₁ and R ₂ represents a linear or branched, saturated or unsaturated, C ₁ -C ₁₂ alkyl, alkenyl, acyl or heteroalkyl group,
Formula (I)

(R ₅ represents a hydrogen atom (H) or R _4. )
A method for producing the compound of